Compositions for the treatment of inflammatory joint diseases and osteoporosis

ABSTRACT

Compositions and pharmaceutical compositions are described which comprise: a component A comprising one or more flavonol glycosides, a component B comprising one or more tetrahydrofolic acid compounds, a component C comprising one or more calcium supplements, and a component D comprising one or more magnesium supplements. Methods of using such compositions and pharmaceutical compositions to treat and/or prevent osteoporosis and/or an inflammatory joint disease are also described.

This invention claims priority of provisional application 60/208,572,filed Jun. 2, 2000.

The present invention relates, e.g., to compositions and pharmaceuticalcompositions for the treatment and/or prevention of osteoporosis and/orinflammatory joint diseases, methods of treating and/or preventingosteoporosis and/or inflammatory joint diseases and the use of theaforementioned composition for the treatment and/or prevention ofosteoporosis and/or inflammatory joint diseases.

BACKGROUND OF THE INVENTION

Osteoporosis (gr: osteon bone; poros hole) is described in general termsas a reduction in bone density with retention of a normal chemicalcomposition. More specifically, osteoporosis is a generalized,progressive diminution of bone density, i.e. bone mass per unit volume,causing skeletal weakness, although the ratio of mineral to organicelements is unchanged. 30 to 40% of the skeletal mass must be lost inorder to reliably diagnose osteoporosis by radiology. Contemporarymedicine distinguishes between primary and secondary osteoporosis (TheMerck Manual of Diagnosis and Therapy, 17th ed., 1999). Primaryosteoporosis includes idiopathic osteoporosis, rare but occurring inchildren and young adults; postmenopausal osteoporosis, occurringbetween the ages of 50 and 75; and involutional or senile osteoporosisassociated with the normal process of aging. It is characterized by apredominant osteoclast activity and a disruption of the feedbackmechanism between the serum calcium level and the parathyroid hormone(PTH) secretion. It occurs mainly uniformly throughout the wholeskeleton. Secondary osteoporosis, accounting for less than 5% of allosteoporosis cases, includes endocrine dysfunctions. It starts mostly atthe main skeleton and progresses centrifugally. Osteoporosis ischaracterized by pain in the respective bones, diffuse back pain,vertebral body collapse, pathological fractures, in particular, fractureof the neck of the femur. The goal of the management of all types ofosteoporosis is therefore to decrease pain, to prevent fractures and tomaintain the body functions.

Osteoporosis is a common clinical feature and common complication inpatients affected with chronic inflammatory diseases with jointmanifestations. These include rheumatoid arthritis (RA), JuvenileRheumatoid Arthritis (JRA), psoriatic arthritis, Reiter's syndrome(reactive arthritis), Crohn's disease, ulcerative colitis, sarcoidosis(Orcel, P.; Cohen-Solal, M.; de Vernejoul, M. C., and Kuntz, D. [Bonedemineralization and cytokines]. Rev Rhum Mal Osteoartic. 1992September; 59(6 Pt 2):16S-22S; Brown, J. H. and Deluca, S. A. Theradiology of rheumatoid arthritis. Am Fam Physician. 1995 Oct;52(5):1372-80; De Vos, M.; De Keyser, F.; Mielants, H.; Cuvelier, C.,and Veys, E. Review article: bone and joint diseases in inflammatorybowel disease. Aliment Pharmacol Ther. 1998 May; 12(5):397-404; Falcini,F.; Trapani, S.; Civinini, R.; Capone, A.; Ermini, M., and Bartolozzi,G. The primary role of steroids on the osteoporosis in juvenilerheumatoid patients evaluated by dual energy X-ray absorptiometry. JEndocrinol Invest. 1996 March; 19(3):165-9; Scutellari, P. N. andOrzincolo, C. Rheumatoid arthritis: sequences. Eur J Radiol. 1998 May;27 Suppl 1:S31-8).

Rheumatoid arthritis is associated with a decrease in bone mass (Cortet,B.; Flipo, R. M.; Blanckaert, F.; Duquesnoy, B.; Marchandise, X., andDelcambre, B. Evaluation of bone mineral density in patients withrheumatoid arthritis. Influence of disease activity and glucocorticoidtherapy. Rev Rhum Engl Ed. 1997 July-Sep. 30, 1997; 64(7-9):451-8).Typical changes of an inflammatory arthritis include juxta-articularosteoporosis, cartilage loss, and cortical or marginal bone erosions(Lawson, J. P. and Steere, A. C. Lyme arthritis: radiologic findings.Radiology. 1985 January; 154(1):37-43; Grassi, W.; De Angelis, R.;Lamanna, G., and Cervini, C. The clinical features of rheumatoidarthritis. Eur J Radiol. 1998 May; 27 Suppl 1:S18-24).

Joint inflammation exerts both local and systemic effects on skeletaltissues. Three forms of bone disease (bone loss) have been described inrheumatoid arthritis, namely: focal bone loss affecting the immediatesubchondral bone and bone at the joint margins; periarticular osteopeniaadjacent to inflamed joints; and generalized osteoporosis involving theaxial and appendicular skeleton (Goldring, S. R. and Gravallese, E. M.Mechanisms of bone loss in inflammatory arthritis: diagnosis andtherapeutic implications. Arthritis Res. 2000; 2(1):33-7).

During chronic inflammatory joint diseases, such as rheumatoidarthritis, synovial cells produce large amounts of cytokines leading toincreased local bone resorption and juxta-articular bone destructions(Orcel, P.; Cohen-Solal, M.; de Vernejoul, M. C., and Kuntz, D. [Bonedemineralization and cytokines]. Rev Rhum Mal Osteoartic. 1992September; 59(6 Pt 2):16S-22S).

The cause of osteoporosis has not been fully clarified. According to onetheory, osteoporosis is a calcium dysfunction and the use of calciumsupplements has been widely suggested. However, so far, noreossification of the osteoporotic bone after calcium therapy could bedemonstrated.

U.S. Pat. No. 5,478,579 describes a method for inducing and enhancingthe absorption of calcium into mammalian bone tissue in order to treatmetabolic calcium deficiencies in bone tissue, in particularosteoporosis. It was found that ossification of mammalian bone tissuecould be enhanced by orally administering to a patient an effective doseof calcium in combination with a flavonol aglycone glycoside. It isbelieved that the flavonol aglycone glycoside affords an advantageousfunction through a chelation delivery system. Flavonols possess abenzene ring structure having available bonds to function as a chelate.Therefore, flavonols, due to their particular molecular structure, arecapable of holding and delivering certain minerals, including calcium,to mammalian bone tissue. Also bone tissue would naturally absorbflavonol glycosides from the blood stream. It is further disclosed thatthe combination of the flavonol aglycone glycoside and calcium leads toan increased bone mineral density which would not have been obtainablethrough the use of simple calcium supplements.

Furthermore, quercetin, which is a related bioflavonoid and differs fromthe aforementioned flavonol compounds in that it does not contain theglycoside residue, has been shown to inhibit tumor necrosis factor-αinduced expression of interleukin 8 (IL-8) and monocyte chemoattractantprotein-1 (MCP-1) in cultured human synovial cells. It was thereforesuggested that quercetin can be used in the treatment of rheumatoidarthritis which is an autoimmune disorder that involves inflammationmainly in synovial tissues of joints (Sato et al., The Journal ofRheumatology, 1997; 24:9, p. 1680). In addition, the relation betweeninterleukins and cytokines and metabolic bone diseases was studied(Pumarino et al., Rev Med Chile 1996; 124: p. 48). It could be shownthat interleukin 1, 6 and 11, transforming growth factor and tumornecrosis factor stimulate osteoclast mediated bone resorption.Interleukin 1 is the most potent bone resorption agent. Although therole of interleukin 1, 6, 11 and the tumor necrosis factors is not quiteclear, they appear to have a depressing effect on bone formation.

Cohen et al. (Israel Journal of Medical Sciences, 17, 1981, p. 1123)investigated the cause of an increased crystallinity index in bonetissue found in iliac crest bone samples from postmenopausalosteoporotic women by chemical analysis. The percentage of crystallinityshould be regarded as an index that assumes that mature bone is onlyapatitic and this provides a measure of crystal size and perfection. Itcould be demonstrated by Cohen et al. that osteoporotic women have lowtotal body magnesium stores. It could also be shown that magnesiumexerts its action as a crystal poison in the nucleation and growth ofapatite and its precrystalline intermediate. Therefore, osteoporoticbone, i.e. bone mineral with a lower magnesium content, has larger andmore perfect crystals and bone mineral with a higher magnesium contenthas smaller and less perfect crystals than normal bone mineral. It wasconsequently suggested that the administering of magnesium supplementsmay be used in osteoporosis therapy.

Homocysteinemia (the accumulation of homocysteine in plasma and tissue)is the result of deficiencies of certain enzymes and/or substratesinvolved in the transmethylation pathways. It is caused by theaccumulation of homocysteine and its two disulfides in plasma and tissue(Mudd et al., The Metabolic Basis of Inherited Disease, New York,McGraw-Hill, 1978, p. 458). Homocysteinemia is associated with juvenilearteriosclerosis, recurrent arterial and venous thromboembolicmanifestations and osteoporosis. The latter may be due to the fact thathomocysteine also interferes with collagen synthesis, and it is thisinteraction that may be significant in the development of defective bonematrix and osteoporosis (Am J Med Sci, 273, 1977, p. 120). Folic acidhas been described as a successful tool for the treatment ofhyperhomocysteinemia (Brattström et al., Metabolism, Vol. 34, No. 11,1985, p. 1073). The metabolite transforming homocysteine to methionineis the active form of folic acid: 5-methyl-tetrahydrafolic acid(5-MTHF). Depending on the degree of methylene tetrahydrofolatereductase (MTHFR) dysfunction, the body can less or more easilytransform the various forms of folates into 5-MTHF.

The effectiveness of the previously proposed compounds or compositionsis, however, generally not satisfactory and there remains a need ofproviding a more effective treatment of osteoporosis and/or inflammatoryjoint diseases.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a new compositionwith improved effects for the treatment and/or the prevention ofosteoporosis and/or inflammatory joint diseases.

Upon further study of the specification and appended claims, furtherobjects and advantages of this invention will become apparent to thoseskilled in the art.

One object has been achieved by a composition comprising the followingcomponents in combination:

a component A comprising one or more flavonol glycosides,

a component B comprising one or more tetrahydrofolic acid compounds,

a component C comprising one or more calcium supplements, and

a component D comprising one or more magnesium supplements.

The present invention provides also a pharmaceutical compositioncomprising the following components in combination:

a component A comprising one or more flavonol glycosides,

a component B comprising one or more tetrahydrofolic acid compounds,

a component C comprising one or more calcium supplements,

a component D comprising one or more magnesium supplements, and

a pharmaceutically suitable carrier, diluent, vehicle and/or exipient.

Moreover, the present invention is directed to a method of treatingand/or preventing osteoporosis and/or an inflammatory joint disease,comprising administering to a mammal in need thereof a therapeuticallyeffective amount of a composition comprising the following components incombination:

a component A comprising one or more flavonol glycosides,

a component B comprising one or more tetrahydrofolic acid compounds,

a component C comprising one or more calcium supplements, and

a component D comprising one or more magnesium supplements.

Finally, the present invention is directed to the use of a compositioncomprising the following components in combination:

a component A comprising one or more flavonol glycosides,

a component B comprising one or more tetrahydrofolate acid compounds,

a component C comprising one or more calcium supplements, and

a component D comprising one or more magnesium supplements for thetreatment and/or prevention of osteoporosis and/or inflammatory jointdiseases.

Firstly, the composition in accordance with the present invention willbe described in more detail.

According to the present invention, the composition comprises acomponent A comprising one or more of flavonol glycosides. The flavonolglycosides contain a flavone skeleton of the following general structureof formula (1):

This skeleton forms the sugar-free part of the flavonoids and is alsogenerally referred to as an aglycone. Any aglycone can be used.Preferably, the aglycone is represented by formula (2) shown below:

wherein R₁ and R₂ are independently hydrogen, hydroxy or a methoxygroup. Preferable examples of the aglycones are quercetin (R₁═OH, R₂═H),kaempferol (R₁═H, R₂═H), myricetin (R₁═OH, R₂═OH) and isorhamnetin(R₁═OCH₃, R₂═H). These aglycones are preferred since they occur innature and are, thus, readily available. Particularly preferred is theaglycone quercetin.

The flavonol glycoside contains a sugar residue which is bound via aglycosidic bond to the aglycone leading to structures of the formulae(3), (4) or (5) shown below.

wherein R₁ and R₂ have the same meaning as described above and Gly is amono- or oligoglycoside residue. Preferably, Gly represents a mono-, di-or triglycoside. The glycoside is preferably selected from hexosylresidues, specifically rhamnesyl, glucosyl, galactosyl and mannosylresidues.

Specific examples of the flavonol glycoside used in the presentinvention include glycosides of quercetin such asquercetin-3-O-galactoside (hyperoside), quercetin-3-O-glucoside(isoquercetin), quercetin-3-O-rhamnoside (quercitrin),quercetin-3-O-rutinoside (rutin), quercetin-7-O-glucoside(quercimeritrin), quercetin-4′-O-glucoside (spiraeosid) andquercetin-3-O-galactoside (hyperin). As an example of a flavonolglycoside of the aglycone kaempferol, kaempferol-3-O-glucoside(astragalin) may be mentioned. Myricetin-3-O-digalactoside is an exampleof a flavonol glycoside of the aglycone myricetin. An example of aflavonol glycoside of the aglycone isorhamnetin isisorhamnetin-3-O-rutinoside (narcissin). The flavonol glycosidesisoquercetin, quercetrin, isoquercetrin, quercimeritrin, spiraeosid,rutin and hyperin are particularly preferred.

The flavonol glycosides may be obtained from any source, e.g., plants,in particular herbs. Herbs known to contain for example quercetinglycosides are described in U.S. Pat. No. 5,478,579.

The composition according to the present invention comprises component Ain an effective amount in order to exert the desired effect in thetreatment and/or prevention of osteoporosis and/or inflammatory jointdiseases.

The composition according to the present invention comprises component Ain an effective amount in order to exert the desired effect in thetreatment and/or prevention of osteoporosis and/or inflammatory jointdiseases. Typically, an amount of about 0.1-25.0 weight % of the total,preferably about 0.2-12.5 weight %, and most preferably about 0.5-10.0weight % is used.

The dosage of component A is preferably selected to comprise 25 to 1000mg, preferably 40 to 500 mg per daily dose.

The composition in accordance with the present invention comprisesfurther a component B comprising one or more tetrahydrofolic acidcompounds.

The tetrahydrofolic acid compound is a derivative of folic acid. Folicacid is metabolized in the body via dihydrofolic acid under the actionof the enzyme dihydrofolate reductase into tetrahydrofolic acid.Examples of the tetrafolic acid compound used in the present inventioninclude tetrahydrofolic acid and derivatives thereof as well asphysiologically acceptable salts thereof. The derivatives are preferablyselected from methyl derivatives or compounds which may be convertedenzymatically into the methyl derivative. It is particularly preferredto use 5-methyltetrahydrofolic acid and physiological acceptable saltsthereof as well as compounds which may be converted in the body into the5-methyl derivative. Thus, the tetrahydrofolic acid compound ispreferably selected from tetrahydrofolic acid, 5-methyltetrahydrofolicacid, 5-formyltetrahydrofolic acid, 10-formyltetrahydrofolic acid,5,10-methylenetetrahydrofolic acid, 5,10-methenyltetrahydrofolic acid orphysiologically acceptable salts thereof. The tetrahydrofolic acidcompound may be used alone or as a mixture. It particularly preferred touse 5-formyltetrahydrofolic acid or physiologically acceptable saltsthereof. Examples of physiologically acceptable salts are alkaline metalor alkaline earth metal salts, such as sodium or calcium salts.

Component B is present in the composition in accordance with theinvention in an amount effective for the treatment and/or prevention ofosteoporosis and/or inflammatory joint diseases. Typically, component Bis present in an amount of about 0.002-0.15 weight % of the total,preferably about 0.004-0.07 weight % and most preferably about 0.01-0.02weight %.

The composition in accordance with the present invention comprisescomponent B preferably in an amount of 400 to 5000 μg, more preferably500 to 4000 μg per daily dose.

The composition in accordance with the present invention containsfurther a component C comprising one or more calcium supplements. Thecalcium supplement is preferably selected from elemental calcium andcalcium compounds. The calcium compound can be selected from calciumoxide and calcium salts of organic or inorganic acids. Preferredexamples of the calcium salts include calcium salts of inorganic acids,e.g. calcium carbonate, calcium salts of organic acids such as calciumcitrate, calcium lactate, calcium gluconate and, in particular, calciumsalts of amino acids such as calcium glycinate and calcium lysinate.

Component C is present in the composition in accordance with theinvention in an amount effective for the treatment and/or prevention ofosteoporosis and/or inflammatory joint diseases. Typically, component Cis used in an amount of about 2.0-50.0 weight % of the total, preferablyabout 5.0-25.0 weight % and most preferably about 10.0-20.0 weight %.

The composition in accordance with the present invention comprisescomponent C preferably in an amount of 400 to 2000 mg, more preferably500 to 800 mg per daily dose.

The composition of the present invention also comprises a component Dcomprising one or more magnesium supplements. The magnesium supplementis preferably selected from elemental magnesium and magnesium compounds.As magnesium compounds, magnesium oxide and magnesium salts of organicor inorganic acids are typically employed. Preferred examples ofmagnesium salts include magnesium salts of inorganic acids, such asmagnesium glycerophosphate and magnesium chloride, magnesium salts oforganic acids such as magnesium citrate, magnesium lactate and magnesiumgluconate and, in particular, magnesium salts of amino acids such asmagnesium glycinate and magnesium taurinate.

Component D is present in the composition of the invention in aneffective amount for the treatment and/or prevention of osteoporosisand/or inflammatory joint diseases. Component D is therefore typicallyused in an amount of about 0.5-30.0 weight % of the total, preferablyabout 1.2-25.0 weight % and most preferably about 2.5-17.5 weight % inthe composition of the present invention.

The composition of the present invention contains component D preferablyin an amount of 100 to 1200 mg, more preferably 300 to 1000 mg per dailydose.

A pharmaceutical composition of the present application comprises theaforementioned components and additionally a pharmaceutically suitablecarrier, diluent, vehicle and/or exipient. The pharmaceuticalcomposition is present in a suitable pharmaceutical form includingsolid, semi-solid, liquid or lyophilized formulations such as tablets,powders, capsules, suppositories, suspensions and aerosols. Preferably,the pharmaceutical form is a tablet or a capsule for oraladministration. The suitable vehicles, carriers, diluents and/orexcipients may be selected depending on the intended use.

Acceptable methods for preparing suitable pharmaceutical forms of thepharmaceutical composition of the present invention are known to thoseskilled in the art. For example, pharmaceutical preparations may beprepared following conventional techniques of the pharmaceutical chemistinvolving steps such as mixing, granulating and compressing thenecessary tablet forms, or mixing, filling and dissolving theingredients as appropriate, to give the desired products for oral,parenteral, topical, transdermal, intravaginal, intranasal,intrabronchial, intraocular, intraaural and/or rectal administration.Illustrative examples of such methods includes those described inRemington's Pharmaceutical Sciences, 18th edition (1990).

Solid or liquid pharmaceutically acceptable carriers, diluents, vehiclesor excipients may be employed in the pharmaceutical compositions of thepresent invention. Illustrative solid carriers include starch, lactose,calcium sulfate dihydrate, terra alba, sucrose, talc, gelatine, agar,pectin, acacia, magnesium stearate and stearic acid. Illustrative liquidcarriers include syrup, peanut oil, olive oil, saline solution andwater. The carrier or diluent may include a suitable prolonged releasematerial such as glycerol monostearate or glycerol distearate, alone orwith other auxiliaries. When a liquid carrier is used, the preparationmay be in the form of a syrup, elixier, emulsion, soft gelatin capsule,sterile injectable liquid (e.g. solution) or a non-aqueous or aqueousliquid suspension.

The aforementioned composition or pharmaceutical composition of thepresent invention is employed in the treatment and/or prevention ofosteoporosis and/or inflammatory joint diseases. Administration of thecomposition of the pharmaceutical composition of the present inventionmay be performed according to any of the accepted modes of adminstrationavailable to those skilled in the art. Illustrative examples of suitablemodes of administration include oral, nasal, parenteral, topical,transdermal, intravaginal, intranasal, intrabronchial, intraocular,intraaural and rectal. Preferably, the mode of adminstration is oral.

The specific dose for each patient depends on a wide variety of factors,for example on the activity of the specific compounds employed, the age,body weight, general state of health, sex, diet, the time and route ofadminstration, the rate of excretion, the medicinal substancecombination and severity of the particular disorder for which thetherapy is applied.

Among the conditions or diseases which can be treated and/or preventedby the composition or pharmaceutical composition of the invention are,e.g., any form of osteoporosis (e.g., primary osteoporosis, including,e.g., idiopathic osteoporosis, postmenopausal osteoporosis, andinvolutional or senile osteoporosis, or secondary osteoporosis,including, e.g., endocrine dysfunctions) and inflammatory joint disease(e.g., rheumatoid arthritis, juvenile arthritis, infectious arthritis,ankylosing spondilitis, osteoarthritis, anrthralgias and other chronicinflammatory diseases associated with joint manifestations).

Advantages of the invention include, e.g., improved joint function(improved joint movement, decrease of morning stiffness, etc.) andreduced signs of inflammation (e.g., pain or swelling).

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any whatsoever.

In the foregoing and in the following examples, all temperatures are setforth uncorrected in degrees Celsius; and, unless otherwise indicated,all parts and percentages are be weight.

The entire disclosure of all applications, patents and publications,cited above is hereby incorporated by referfence.

EXAMPLES Example 1

An oral formulation according to the invention is obtained by mixing:

Quercetin-3-O-glucoside (isoquercetin)—500 mg

5-methyltetrahydrofolic acid calcium salt—800 μg

Calcium citrate tetrahydrate—4000 mg (844 mg Ca)

Magnesium chloride hexahydrate—3000 mg (360 mg Mg)

Example 2

An oral formulation according to the present invention is obtained bymixing:

Quercetin-3-O-glucoside (isoquercetin)—200 mg

5-methyltetrahydrofolic acid calcium salt—400 μg

Calcium lysinate (Ca, 12%)—1600 mg

Calcium glycinate (Ca, 20%)—200 mg

Magnesium citrate, dibasic (Mg, 11%)—1000 mg

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A composition comprising: a component Acomprising one or more flavonol glycosides, a component B comprising oneor more tetrahydrofolic acid compounds, a component C comprising one ormore calcium supplements selected from calcium carbonate, a calciumcitrate, calcium lactate, calcium gluconate, or a calcium salt of anamino acid and a component D comprising one or more magnesiumsupplements selected from magnesium oxide, magnesium glycerophosphate,nagnesium chloride, magnesium citrate, magnesium lactate, magnesiumgluconate or a magnesium salt of an amino acid.
 2. The compositionaccording to claim 1, wherein component A comprises one or more of aflavonol mono-, di- or triglycoside containing the aglycone, quercetin.3. The composition according to claim 1, wherein component A isisoquercetin, quercitrin, isoquercitrin, quercimeritrin, spiraeosid,rutin or hyperin.
 4. The composition according to claim 1, whereincomponent A is 0.1-25.0 weight % of the total composition.
 5. Thecomposition according to claim 1, wherein component B comprises one ormore of tetrahydrofolic acid, 5-methyltetrahydrofolic acid,5-formyltetrahydrofolic acid, 10-formyltetrahydrofolic acid, or5,10-methylenetetrahydrofolic acid, or 5,10-methenyltetrahydrofolicacid, or a physiologically acceptable salt thereof.
 6. The compositionaccording to claim 1, wherein component B comprises5-formyl-tetrahydrofolic acid or a physiologically acceptable saltthereof.
 7. The composition according to claim 1, wherein component B is0.002-0.15 weight % of the total composition.
 8. The compositionaccording to claim 1, wherein component C is calcium citratetetrahydrate.
 9. The composition according to claim 1, wherein componentC is 2.0-50.0 weight % of the total composition.
 10. The compositionaccording to claim 1, wherein said component D is magnesium gluconate.11. The composition according to claim 1, wherein component D is0.5-30.0 weight % of the total composition.
 12. A method for thetreatment of osteoporosis, rheumatoid arthritis, juvenile rheumatoidarthritis, psoriatic arthritis, infectious arthritis, ankylosingspondilitis, osteoarthritis, anrthralgias, Reitzer's syndrome, Crohn'sdisease, ulcerative colitis and/or sarcoidosis comprising administeringto a patient in need thereof an effective amount of a compositionaccording to claim
 1. 13. A pharmaceutical composition comprising: acomponent A comprising one or more flavonol glycosides, a component Bcomprising one or more tetrahydrofolic acid compounds, a component Ccomprising one or more calcium supplements selected from calciumcarbonate, calcium citrate, calcium lactate, calcium gluconate, or acalcium salt of an amino acid and a component D comprising one or moremagnesium supplements selected from magnesium oxide, magnesiumglycerophosphate, magnesium chloride, magnesium citrate, magnesiumlactate, magnesium gluconate or a magnesium salt of an amino acid. 14.The pharmaceutical composition according to claim 13, wherein componentA comprises one or more of a flavonol mono-, di- or triglycosidecontaining the aglycone, quercetin.
 15. The pharmaceutically compositionaccording to claim 13, wherein component A is isoquercetin, quercitrin,isoquercitrin, quercimeritrin, spiraeosid, rutin or hyperin.
 16. Thepharmaceutical composition according to claim 13, wherein component A is0.1-25.0 weight % of the total composition.
 17. The pharmaceuticalcomposition according to claim 13, wherein component B comprises one ormore of tetrahydrofolic acid, 5-methyltetrahydrofolic acid,5-formyltetrahydrofolic acid, or 10-formyltetrahydrofolic acid,5,10-methylenetetrahydrofolic acid, or 5,10-methenyltetrahydrofolicacid, or a physiologically acceptable salt thereof.
 18. Thepharmaceutical composition according to claim 13, wherein component Bcomprises 5-formyl-tetrahydrofolic acid or a physiologically acceptablesalt thereof.
 19. The pharmaceutical composition according to claim 13,wherein component B is 0.002-0.15 weight % of the total composition. 20.The pharmaceutical composition according to claim 13, wherein componentC is calcium citrate.
 21. The pharmaceutical composition according toclaim 13, wherein component C is 2.0-50.0 weight % of the totalcomposition.
 22. The composition according to claim 13, wherein saidcomponent D is magnesium gluconate.
 23. The pharmaceutical compositionaccording to claim 13, wherein component D is 0.5-30.0 weight % of thetotal composition.
 24. A method for the treatment of osteoporosisrheumatoid arthritis ,juvenile rheumatoid arthritis, psoriaticarthritis, infectious arthritis, ankylosing spondilitis, osteoarthritis,anrthralgias, Reitzer's syndrome, Crohn's disease, ulcerative colitisand/or sarcoidosis comprising administering to a patient in need thereofan effective amount of a composition according to claim
 13. 25. A methodof treating osteoporosis comprising administering to a mammal in needthereof a therapeutically effective amount of a composition comprising:a component A comprising one or more flavonol glycosides, a component Bcomprising one or more tetrahydrofolic acid compounds, a component Ccomprising one or more calcium supplements selected from calciumcarbonate, calcium citrate, calcium lactate, calcium gluconate, or acalcium salt of an amino acid and a component D comprising one or moremagnesium supplements selected from magnesium oxide, magnesiumglycerophosphate, magnesium chloride, magnesium citrate, magnesiumlactate, magnesium gluconate or a magnesium salt of an amino acid. 26.The method according to claim 25, wherein component A comprises one ormore of a flavonol mono-, di- or triglycoside containing the aglycone,quercetin.
 27. The method according to claim 25, wherein component Acomprises one or more of isoquercetin, quercitrin, isoquercitrin,quercimeritrin, spiraeosid, rutin or hyperin.
 28. The method accordingto claim 25, wherein component A is 0.1-25.0 weight % of the totalcomposition.
 29. The method according to claim 25, wherein component Bcomprises one or more of tetrahydrofolic acid, 5-methyltetrahydrofolicacid, 5-formyltetrahydrofolic acid, 10-formyltetrahydrofolic acid,5,10-methylenetetrahydrofolic acid, or 5,10-methenyltetrahydrofolicacid, or a physiologically acceptable salt thereof.
 30. The methodaccording to claim 25, wherein component B comprises5-formyltetrahydrofolic acid or a physiologically salt thereof.
 31. Themethod according to claim 25, wherein component B is 0.002-0.15 weight %of the total composition.
 32. The method according to claim 25, whereincomponent C is calcium citrate.
 33. The method according to claim 25,wherein component C is 2.0-50.0 weight % of the total composition. 34.The method according to claim 25, wherein said component D is magnesiumgluconate.
 35. The method according to claim 25, wherein component D is0.5-30.0 weight % of the total composition.
 36. The method according toclaim 25, wherein the mammal is a human.
 37. A method of treating aninflammatory disease comprising administering to a mammal in needthereof a therapeutic effective amount of a composition comprising: acomponent A comprising one or more flavonol glycosides, a component Bcomprising one or more tetrahydrofolate acid compounds, a component Ccomprising one or more calcium supplements selected from calciumcarbonate, calcium citrate, calcium lactate, calcium gluconate, or acalcium salt of an amino acid and p1 a component D comprising one ormore magnesium supplements selected from magnesium oxide, magnesiumglycerophosphate, magnesium chloride, magnesium citrate, magnesiumlactate, magnesium gluconate or a magnesium salt of an amino acid. 38.The method according to claim 37, wherein component A comprises one ormore of a flavonol mono-, di- or triglycoside containing the aglycone,quercetin.
 39. The method according to claim 37, wherein component Acomprises one or more of isoquercetin, quercitrin, isoquercitrin,quercimeritrin, spiraeosid, rutin or hyperin.
 40. The method accordingto claim 37, wherein component A is 0.1-25.0 weight % of the totalcomposition.
 41. The method according to claim 37, wherein component Bcomprises one or more of tetrahydrofolic acid, 5-methyltetrahydrofolicacid, 5-formyltetrahydrofolic acid, 10-formyltetrahydrofolic acid,5,10-methylenetetrahydrofolic acid, or 5,10-methenyltetrahydrofolicacid, or a physiologically acceptable salt thereof.
 42. The methodaccording to claim 37, wherein component B comprises5-formyltetrahydrofolic acid or a physiologically acceptable saltthereof.
 43. The method according to claim 37, wherein component B is0.002-0.15 weight % of the total composition.
 44. The method accordingto claim 37, wherein component C is calcium citrate.
 45. The methodaccording to claim 43, wherein component C is 2.0-50.0 weight % of thetotal composition.
 46. The method according to claim 37, whereincomponent D is magnesium gluconate.
 47. The method according to claim37, wherein component D is 0.5-30.0 weight % of the total composition.48. The method according to claim 37, wherein the mammal is human. 49.The method according to claim 37, wherein said inflammatory disease isrheumatoid arthritis, juvenile rheumatoid arthritis, psoriaticarthritis, infectious arthritis, ankylosing spondilitis, osteoarthritis,anrthralgias, Reitzer's syndrome, Crohn's disease, ulcerative colitisand/or sarcoidosis.
 50. A method according to claim 24, wherein saidmethod is for treating rheumatoid arthritis ,juvenile rheumatoidarthritis, psoriatic arthritis, infectious arthritis, ankylosingspondilitis, osteoarthritis, anrthralgias, Reitzer's syndrome, Crohn'sdisease, ulcerative colitis and/or sarcoidosis.